SCIENCE: Aging-related protein's function unraveled in fruit flies

Research may be applicable to humans

Scientists seeking understanding of the human aging process say
they have found important new evidence in fruit flies. The research
helps explain why a life-extension therapy works in mice, and
theoretically could work in humans.

A protein called sestrin plays a key role in regulating aging
and metabolism, said the scientists from UC San Diego. Their work
is the cover story in Friday's issue of the prestigious journal
Science.

When the gene that makes the sestrin protein is inactivated,
Drosophila fruit flies experience health problems uncannily similar
to what happens in aging humans, said Michael Karin, a UCSD
professor who led the study.

Closely related sestrin proteins also are found in mice and
other mammals, including humans. The research could eventually lead
to drugs to slow age-related degeneration, Karin said.

Early aging

Fruit flies bred with an inactivated sestrin gene began showing
signs of premature aging in what is supposedly the prime of a fruit
fly's life, Karin said.

"They start accumulating triglycerides when they are 20 days
old," Karin said. "Since a fly lives about 90 to 120 days, that’s
like a 20-year-old individual. They start developing different
types of muscle degeneration, both striated muscle (for voluntary
movement) and cardiac muscle (involuntary)."

Moreover, an unusually high percentage of mitochondria, the main
energy source in cells, is defective in these flies.

"Muscle twitches all the time, especially cardiac muscle," Karin
said. "So it does a lot of work, and the mitochondria have to
generate all the energy for the muscle contraction, and they
probably get old and damaged."

The process of autophagy, which removes old mitochondria and
replaces them with new ones, is also disrupted, Karin said.
Autophagy, which "recycles" the substances in mitochondria, is very
widespread in life, Karin said. It occurs not only in fruit flies,
but also in mammals and even yeast.

Most of the damage was prevented in the sestrin-deficient flies
by giving them vitamin E, an antioxidant.

Many functions

Sestrins are produced in response to stress. They play multiple
major roles, which makes discerning their functions difficult,
according to Karin:

-- They appear to act as antioxidants, produced in response to
DNA damage. In an earlier paper, Karin said sestrins are part of a
cancer-protective process activated by a gene called p53. The p53
is defective in more than half of human cancers.

-- In addition, sestrins activate another protein, called AMPK,
that also can be activated by a calorie-restricted diet. Calorie
restriction has been found to extend life in a number of
animals.

-- Sestrins inhibit an enzyme called TOR. This enzyme is also
inhibited by an immunosuppressant drug called rapamycin, given to
those who have had organ transplants. (TOR stands for target of
rapamycin).

Male mice given rapamycin late in life lived 14 percent longer
than a control group; the life of female mice was extended 9
percent. This recent research is "all the rage" in studies about
how to slow aging, Karin said.

"The question is, if it you give it (rapamycin) for a very long
time, what would be the side effects?" Karin said.

Onward to mice

With so much activity to trace, the researchers chose to
experiment on fruit flies because it takes less work than studying
mammals, Karin said. Fruit flies reproduce faster than mice and
have only one sestrin protein, while mammals have three kinds, he
said.

Some studies have been done in mammalian cell cultures, Karin
said, but studies in live animals are considered more definitive.
Now with the evidence from the fruit flies, studies in live mice
are under way.

Sestrins are "highly conserved," Karin said, meaning that they
are pretty much the same in creatures that have a distant common
ancestor. Such features are presumed to have important, basic
biological functions. For example, certain genes that govern heart
formation and function are conserved between fruit flies and
humans.

If features are highly conserved between such distantly related
creatures as fruit flies and mice, scientists say they are also
likely to be highly conserved between mice and humans. That's
because humans and mice share a much more recent common ancestor
than they do with fruit flies.